PROJECT SUMMARY Nanotechnologies occupy a special place in biomedical research. A large variety of nanoparticles have been proposed to address medical needs. Nanoemulsions constitute one class of nanoparticles with specific applications in both drug delivery and imaging. Nanoemulsions are composed of nanodroplets of lipid, in the size range 50-300 nm, that are stabilized with a surfactant to form very stable emulsions in aqueous solution. The lipid phase can be a pure drug, if the drug is a liquid, or it can be a solution of the drug to be delivered in a FDA-approved liquid lipid. Nanoemulsions are very promising for delivery purposes because of the large amounts of drugs that can be encapsulated in the lipid droplets. Nevertheless, nanoemulsions are noncovalent aggregates not in thermodynamic equilibrium and as such their stability in physiological conditions, especially in blood, is directly related to the interaction of the stabilizing surfactants with the blood hydrophobic components. This proposal addresses the need of preparing highly stable drug-containing nanoemulsions that will allow effective time release and drug delivery. These medically important properties of emulsions are achieved by using a novel class of triphilic polymers. These polymers are composed of a hydrophobic domain such as a hydrocarbon chain containing up to 18 carbon atoms, a fluorous domain, containing between 8 and 16 fluorine-bearing carbon atoms, and a hydrophilic domain composed of a poly(ethylene glycol) to ensure water-solubility and biocompatibility. The fluorous domain in these polymers plays a very special role. Fluorocarbons have the peculiar property of being both hydrophobic and lipophobic. They self-segregate in what is called the fluorous phase. Thus, the structure of a particle in the proposed nanoemulsions can be envisioned as being made of an internal lipid droplet containing the drug to be delivered. This droplet is surrounded by a shell of the triphilic polymer with the polymer hydrophobic domain directly in contact with the lipid particle. Next, is a fluorous shell composed by the intermediate fluorocarbon in the polymer. The fluorous chains will shield the internal hydrophobic droplet, dramatically increasing the stability of the nanoemulsion. The fluorous shell also makes possible to modulate the time release of the drug from the emulsion. Preliminary results show a high drug loading capacity and effective drug time-release. Finally, we propose to study the safety of the proposed polymers. Using the Zebrafish nanotoxicity model we have found that fluorocarbon- containing are safe to use if the fluorocarbon is attached to the rest of the molecule through very stable functionalities such as an ether linkage, and if the molecules are pegylated. The structure of all proposed polymers reflects these findings. Nevertheless, we will also perform similar toxicity studies on all the new polymers described in this proposal. We anticipate that these new nanoemulsions will be effective in the delivery of anticancer agents and in the sustained delivery of hydrophobic antifungals and antibiotics.